There is an enormous unmet need for disease-modifying drugs that affect the pathogenesis of Alzheimer's disease (AD). Currently available drugs provide only modest cognitive improvement and may delay the onset of disability, but do not halt the disease process. AD is the most common form of dementia, deeply affecting the lives of an estimated 4.5 million Americans, with an economic cost exceeding $100 billion. In this and the subsequent STTR Phase II project, Mithridion, Inc, a University of Wisconsin, Madison (UW) spin-out company, will collaborate with UW to attempt to discover and develop first-of-class disease-modifying therapies for AD. An effective therapy of this type would bring enormous benefits to affected individuals, relatives, caregivers, healthcare providers and society as a whole. The project builds upon the discovery in UW of a novel natural neuroprotective mechanism, protecting against the toxicity of AB, the amyloid protein precursor-derived agent implicated in the pathogenesis of AD. Protection results from the coordinated expression of transthyretin (TTR), insulin-like growth factor-2 (IGF-2) and other growth factor-related genes. Naturally occurring activators of this pathway have been identified, structurally characterized in patented by UW. These are very small peptides, providing excellent starting points for the design and development of peptidic and peptidomimetic drug candidates. We have demonstrated the relevance of the neuroprotective mechanism and its activators in vivo in mouse models, and in vitro in both mouse and human primary brain cultures. In Phase I, we propose to establish the feasibility of this novel approach by further validating the original findings in a second transgenic mouse model, and by demonstrating improved in vitro drug evaluation tests, already available as prototypes from the UW lab. We will then test an initial series of synthetic compounds, designed around the chemical structure of the natural activator to validate the tests and establish feasibility of structure-based drug design in Phase II. We will measure expression of TTR and other surrogate markers at RNA and protein levels. In a separate (non-STTR) project, further validation work will be done in human brain tissue in vitro. In the subsequent Phase II, we propose to undertake an integrated drug design and development project, based on the tests developed and validated in Phase I, the starting point being the hypotheses for drug design developed in Phase I. [unreadable] [unreadable] [unreadable]